Ilona J. Frieden and Sheilagh M. Maguiness
VASCULAR ANOMALIES: CLASSIFICATION
The International Society of the Study of Vascular Anomalies (ISSVA) divided vascular anomalies into malformations or tumors, and the vast majority of vascular lesions can be classified using this schema (Table 364-1). Vascular tumors and malformations can usually be distinguished from one another based on clinical appearance and growth characteristics (Table 364-2). If diagnosis is unclear observation over time, imaging studies or even biopsy may be required.
CLINICAL MANIFESTATIONS AND SUBTYPES
The most common vascular tumor is infantile hemangioma (IH), present in approximately 4% of infants and more common in females, Caucasians, preterm infants (particularly in those weighing < 1500 g) and infants of multiple gestations.2 A key clinical feature is whether hemangiomas are localized (eg, arising as a nodule or small area of skin involvement as if from a central focus) or segmental (involving a territory of skin) (Figs. 364-1A, B). Segmental hemangiomas are much more likely to cause complications, often need referral and/or treatment, and have associated extracutaneous abnormalities.2
Table 364-1. Updated International Society of the Study of Vascular Anomalies Classification of Vascular Anomalies
IHs are characteristically either absent or present at birth as precursor lesions such as a telangiectatic, bruiselike area or skin pallor resembling nevus anemicus. The clinical appearance of hemangiomas after proliferation depends on their location within the skin. Superficial lesions appear as brightly erythematous well-demarcated plaques, whereas deep hemangiomas present as rubbery or soft, blue-hued subcutaneous nodules. Mixed IHs have features of both.
Table 364-2. Major Differences between Vascular Tumors and Malformations
FIGURE 364-1. A: Segmental hemangioma of the S1 distribution. B: Solitary, localized, superficial infantile hemangioma. C: Rapidly involuting congenital hemangioma. D: Tufted angioma in a patient with Kasabach-Merritt phenomenon; note associated hypertrichosis.
BIOLOGY AND GROWTH CHARACTERISTICS
Most IHs undergo a characteristic proliferative phase during the first weeks to months of life, and growth is typically completed by 4 to 6 months of age, except in the case of deep or large segmental IHs, where the proliferation phase may last up to a year and, in rare instances, even longer.3 The rate of involution of IHs is considerably slower than the growth phase: most small hemangiomas have involuted significantly by 2 to 3 years of age, whereas larger, bulkier lesion may take several more years to complete involution.
Involution, however, does not always imply resolution without clinical sequelae. A significant minority of IHs resolve, leaving behind fibrofatty tissue, telangiectasias, atrophic, or stretch mark-like residua, which if located in visable areas such as the central face can cause permanent disfigurement.
The pathogenesis of IHs is not well understood. More recent evidence points to immunohistochemical and genetic similarities to placental blood vessels, including characteristic staining for erythrocyte-type glucose transporter protein GLUT-1.4 This can be used as a diagnostic tool to separate IHs from other vascular anomalies.
Pediatricians and dermatologists are aware that the vast majority of infantile hemangiomas resolve without incident. However, prospective studies have determined that complications occur in up to 24% of hemangiomas in a referral population.5 The most important predictors of potential complications are size, anatomic location, and segmental subtype. Ulceration is the most common complication of infantile hemangiomas, occurring in approximately 15% of cases and more commonly in areas of moisture and friction, such as in the perioral area and in up to 50% of lesions involving the perineum. Hemangioma size is another important predictor of complication: those larger than 35 cm2have a higher rate of complications.5
Segmental facial hemangiomas (Fig. 364-1A) can be associated with a group of structural malformations known as PHACE, an acronym for posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. When midline sternal defects or supraumbilical abdominal raphe are present, the condition is referred to as PHACES syndrome. This more recently described neurocutaneous syndrome may actually be as common as Sturge-Weber syndrome6 and has an female-to-male ratio of 8:1. Most cases are associated with segmental hemangiomas with involvement of either S1 or S3 segments (eFig. 364.1 ). The diagnosis of PHACES is rendered in patients having a segmental facial hemangioma and one other associated feature.
Analogous to facial segmental hemangiomas, segmental hemangioma involving the lumbosacral regions can be associated with spinal dysraphism and genitourinary anomalies.
Specific anatomic locations can provide clues to possible complications. Hemangiomas located in the periorbital area can cause astigmatism and visual axis obstruction leading to amblyopia and should be followed closely, particularly during the growth phase (eg, the first few months of life). Nasal tip hemangiomas can cause splaying of the alar cartilage and are often slow to involute, causing permanent distortion of the normal anatomy which can be difficult to surgically correct. Large hemangiomas on the ear may cause temporary conductive hearing loss or deformation of the cartilage. Perioral and perianal (mucosal) hemangiomas have a high rate of ulceration,8 causing significant pain. In addition, IH located on the lip may cause distortion of the vermillion border or Cupid’s bow, leading to altered anatomy and disfigurement. Hemangiomas located in the so-called beard distribution of the mandible, chin, and upper neck have a high risk of associated airway involvement. Infants with airway hemangiomas often present with stridor or “noisy breathing” between 6 and 12 weeks of age; aggressive systemic treatment is warranted in these cases. Aggressive systemic and surgical management can help avoid the need for tracheostomy in the majority of patients.
Infants with five or more hemangiomas or large segmental hemangiomas have a greater risk of extracutaneous hemangiomas, particularly involving the liver. Most often, liver hemangiomas are small and asymptomatic and can be followed with ultrasound until stabilization is documented. If present, Doppler examination with assessment of flow within the hepatic vein and artery can help determine risk of hemodynamic compromise. In rare instances, extensive intra-abdominal hemangiomas can cause failure to thrive and high-output cardiac failure. A rare complication is an acquired form of hypothyroidism due to hemangioma production of type 3 iodothryonine deiodinase.9
The major goals in management of hemangiomas are to prevent life- or function-threatening emergencies, adequately treat ulceration, anticipate and attempt to manage potential disfigurement, and minimize psychosocial stress for the patient and family. Overly aggressive, potentially scarring surgical procedures early in the proliferative phases of hemangiomas should be avoided in tumors where the likelihood of involution without significant cosmetic impairment is expected.
Up to 15% of hemangiomas ulcerate,8 often in the early proliferative stage. Ulceration occurs most frequently on mucosal sites (lip and perineum) in segmental or large lesions. Pain is nearly always present and should be adequately treated with analgesia. Local wound care is important in the management of ulcerated hemangiomas. Crust should be removed with warm compresses and, if necessary, dilute hydrogen peroxide solution. Topical metrogel is anecdotally effective and should be applied to ulcerated areas daily. Protective barrier agents such as petrolatum should be used liberally, along with nonstick dressings. Occlusion helps decrease pain and speed healing. In severe cases, topical becalpermin gel (platelet-derived growth factor) is useful in stimulating granulation tissue and healing.10 Pulsed dye laser can also be used as a treatment for ulceration. For some sites, surgical excision may be a good treatment for ulceration because a scar will be present in any case.
Corticosteroids are a mainstay of treatment of hemangiomas, used topically, intralesionally, or orally. Very potent (class 1) topical steroids are occasionally helpful for very flat hemangiomas in prominent anatomic locations. Intralesional injections of triamcinolone may be useful for small, well-localized hemangiomas in difficult locations, such as the lip or nasal tip, and for treating periorbital hemangiomas. Potential complications include skin atrophy, infection, and systemic absorption and, for periorbital lesions, rarely, retinal artery occlusion. Oral corticosteroids are a first-line therapy for life- or function-threatening hemangiomas. Oral prednisolone is typically administered in doses of 2 to 3 mg/kg/day. At least two thirds of patients respond with shrinkage or stabilization in size of the hemangioma. Therapy for several months is often necessary, with a gradual taper toward the end. Potential side effects include irritability, hypertension, immunosuppression, and growth retardation, but treatment is usually well tolerated, with catch-up growth occurring after cessation. High-dose corticosteroids can predispose patients to infections such as pneumocystis pneumonia; prophylaxis with trimethoprim/sulfamethoxazole is often given as adjunctive therapy. Gastroesophageal reflux may also result; ranitidine or proton pump inhibitors can be helpful.
Since 2008, more than 30 case reports have demonstrated efficacy of propranolol in the treatment of hemangiomas. Controlled randomized trials have not yet been performed. Propranolol is typically administered in doses of 1 to 3 mg/kg/day divided into 2 or 3 doses. Favorable responses are often noted within days of starting the medication. As with steroids, administration for many months is often necessary. Potential side effects include hypoglycemia (particularly with preoperative fasting or poor feeding), bradycardia, hypotension, nightmares, and hypothermia. A possible concern for propranolol use in patients with PHACE syndrome is that hypotension or bradycardia may reduce an already compromised cerebrovascular flow. With the introduction of propranolol, interferon alpha use will likely decline, due to its potential neurotoxicity in young infants.
Laser therapy, particularly the flashlamp pumped pulsed dye laser (PDL), can be effective in treating relatively flat, superficial hemangiomas or in “mopping up” residual telangiectasias, but is ineffective in treating thicker and deeper lesions because of its limited depth of penetration. The risk of scarring is higher than in its use for port wine stains, particularly in the proliferative phase. Other laser systems have also been used for treating hemangiomas, including intralesional Nd-YAG and other continuous-wave laser systems. These lasers are more operator dependent and have a higher risk of scarring than PDL but may be appropriate in selected cases.
Reconstructive surgical techniques are well accepted for revising permanent scars left after hemangioma involution. Earlier surgical excision is more controversial but is probably reasonable in hemangiomas with a very high likelihood of leaving a baglike fibrofatty residual (eg, pedunculated hemangiomas) or other obvious scar. If feasible, surgery is also recommended for function-threatening hemangiomas that have failed medical therapy. If significant uncertainty is present, it is usually best to delay a decision until 3 to 4 years of age and reevaluate.
OTHER VASCULAR TUMORS
Congenital hemangiomas (CHs) are benign vascular lesions distinct from infantile hemangiomas (IHs). They are present at birth and have different growth and biologic characteristics that help differentiate them from IHs. Unlike IHs, the blood vessels of CHs do not express GLUT-1. CHs can present in two distinct forms: rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH). Clinical overlap between these two forms has led some authors to use the term nonproliferative congenital hemangioma. Both conditions present as a fully formed vascular tumor at birth (Fig. 364-1C). RICHs tend to be more exophytic at birth, and rapid involution during the first year of life is characteristic. NICHs are typically flatter at birth, presenting as warm red-blue vascular plaques with overlying telangiectasias and surrounding areas of vasoconstriction. They typically persist unchanged through life.
Pyogenic granulomas (PGs), also known as lobular capillary hemangiomas, are common vascular tumors during childhood. They may develop spontaneously or in response to trauma, varying in size from a few millimeters to 1 to 2 centimeters. They usually grow rapidly, presenting as a friable red papule or nodule that bleeds profusely and repeatedly despite its small size. Over time, lesions often have a black hemorrhagic crust and a peripheral collarette of scale. Differential diagnosis includes infantile hemangioma, wart, and Spitz nevi. Spontaneous resolution is rare, but symptomatic lesions may be removed by shave excision or currettage, with light electro-cautery of the base.
Spider angiomas are common, benign vascular neoplasms in children. They may arise spontaneously or be preceded by a history of trauma, sun exposure, or insect bite. Lesions present as small 2- to 5-millimeter, brightly erythematous, completely blanchable papules with a central punctum surrounded by radiating vessels, and are most often located on exposed areas such as the face and hands. They may involute spontaneously or persist indefinitely. They are completely benign, and unless more than a few are present, pose no associated clinical concerns, and can easily be removed for cosmetic purposes with the pulsed dye laser (treatment of choice), or, if unavailable, electrocautery.
Angiokeratomas are another type of benign vascular tumor that develops in the superficial dermis causing characteristic hyperkeratosis in the overlying epidermis.
Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors that share overlapping clinical features. These tumors are now recognized to be the cause of virtually all cases of Kasabach-Merritt phenomenon (KMP), a condition formerly believed to be due to infantile hemangiomas. KHE and TA (Fig. 364-1D) typically present early in childhood as firm, ill-defined, violaceous-to-purpuric, indurated plaques/nodules, sometimes associated with hypertrichosis or hyperhidrosis. Immunohistochemical studies show that both tumors are likely to be derived from progenitor stem cells sharing features of both lymphatic and blood vessel endothelial lineage.11 Small tumors of KHE and TA less than 2 to 3 centimeters have a benign course, but larger tumors often exhibit locally invasive, aggressive clinical behavior. KMP, the most feared complication, is a consumptive coagulopathy, thrombocytopenia, decreased fibrinogen, and elevated D-dimers. No single treatment is uniformly effective; however, systemic corticosteroids and vincristine are the most common treatments currently used. Platelet transfusions should not be given even if the thrombocytopenia is profound, unless patients are actively bleeding or require a surgical intervention, because they seem to promote tumor growth and worsening of the condition with only very transient rises in platelet counts. The coagulopathy of KMP is distinct from that observed in patients with extensive venous malformations.
Vascular malformations are congenital anomalies caused by errors in vascular morphogenesis. They are present at birth even if unapparent in the neonatal period. They typically grow commensurate with somatic growth, but over time may enlarge or thicken due to progressive vessel dilatation (Table 364-2).
Capillary malformations are vascular anomalies that are typically noted at the time of birth. The most common of these is the nevus simplex (salmon patch), presenting as a pink patch variably involving the glabella, eyelid, perinasal area, upper lip, and nape. They typically fade by age 2 years, although those on the nape often persist indefinitely.
Port wine stains (PWSs; nevus flammeus) are congenital capillary malformations (CMs), which unlike nevus simplex, are true malformations and persist throughout life. PWSs possess an increased number of dilated capillaries within the dermis, both in the superficial and deep dermal plexi. They are present at birth and can occur in any size or on any location. They tend to remain flat during childhood but can thicken over time, and those involving the perioral area can cause gingival and soft tissue hypertrophy. The risk of extra-cutaneous associations depends on anatomic location. Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by a PWS, ipsalateral cerebral vascular malformation, and ophthalmologic disease (glaucoma, increased retinal vascularity). SWS only occurs with V1 involvement, and the risk increases to as high as 25% or higher with larger PWS (eg, including V1 and V2 or bilateral PWS are present) (Fig. 364-2B). Patients with PWS involving either upper or lower eyelids should receive lifelong regular ophthalmologic evaluations to monitor for glaucoma. Klippel-Trénaunay syndrome (KTS) (Fig. 364-2A) is characterized by a CM, ipsilateral hemihypertrophy, and venous varicosties. When leg involvement is present, limb lengths should be monitored periodically because limb overgrowth may develop over time.
The flashlamp pumped pulsed dye laser (PDL) has proven safe and effective in the treatment of port wine stain (PWS), even in very young children. Generally, up to 6 to 20 treatments are required, and results vary from complete clearance to significant lightening in most cases. For unknown reasons, lesions in the V2 distribution of the face respond less well.
Venous malformations (VMs) are comprised of ectatic, malformed veins, and are often evident at birth or present in childhood as soft, compressible, blue-hued nodules that swell with dependency. VMs have previously been confused with hemangiomas, and indeed the term “cavernous hemangioma” was once used as a catch-all term for any benign blue soft tissue growth, including VMs and deep infantile hemangiomas; however, this term should be avoided. VMs can involve skin, muscle, and, occasionally, bone and other sites, including the gastrointestinal tract (Fig. 364-2C). V M s are seen in multiple syndromes, including Maffucci syndrome, Proteus and Proteus-like syndrome, Familial cutaneous and mucosal venous malformation (VMCM), and Banayan-Riley-Ruvalcaba syndrome.
VMs have many potential complications, some of which can be life threatening. Pain and swelling are very common. Coagulopathy is common in large VMs, particularly those with intramuscular disease, and is characterized by a low-grade, localized intravascular coagulation, which can lead to clotting and resultant “phleboliths” within the malformation, as well as low fibrinogen, elevated Ddimers, and a resultant bleeding diathesis systemically. The coagulopathy seen in VMs is distinct from that in Kasabach-Merritt phenomenon. Impact on quality of life can also be profound due to complications and progressive disfigurement.
FIGURE 364-2. A: Port wine stain of the leg associated with Klippel-Trénaunay syndrome. B: Port wine stain of the V1 distribution of the face in a patient with Sturge-Weber syndrome. C: Venous malformation of the face.
Several types of lymphatic malformations (LMs) occur in infancy and childhood and are due to aberrant lymphatic channels. LMs can be superficial, confined to the skin and mucosa (so-called lymphangioma circumscripta), or deep and visceral. Superficial LMs present as small, flesh-colored, fluid-filled blebs (frog’s spawn) clustered together with focal red-to-black hemorrhagic areas. In superficial lesions, microcysts predominate. Deeper LMs may be macrocystic, micro-cystic, or have features of both. Macrocystic lesions are large collections of lymphatic fluid and are also known by the term “cystic hygroma.” Microcystic LMs characteristically have smaller infiltrative “spongelike” channels and tend to cause more complications, such as bleeding or chronic drainage of lymphatic fluid. LMs are associated with recurrent cellulitis. Long-standing lesions develop fibrosis/scarring and lymphedema. Treatment of LMs is very difficult due to deep extension and propensity to recur after surgery. In localized superficial lesions, surgery, sclerotherapy, laser ablation, or even liposuction has been used as treatment; however, results are often unsatisfactory in larger or macrocystic lesions. In some cases, compression garments are very helpful.
Congenital lymphedema is a characteristic of Millroy disease (familial lymphedema, OMIM #153100) and is associated with mutations in VEGFR3 in some families. Other syndromes associated with congenital lymphedema include Noonan syndrome and Turner syndrome.
Arteriovenous malformations (AVMs) are rare, high-flow vascular lesions with direct arteriovenous shunting. Most AVMs occur in the cervicofacial region (70%) and are present at birth with progression or dilatation over time. AVMs are the most dangerous of all vascular malformations and can be complicated (depending on size and location) by high output cardiac failure, bony erosion, and catastrophic bleeding. AVMs are seen in multiple syndromes. Parkes-Weber syndrome is the association of AVM (multiple AV fistulae) with ipsalateral hemihypertrophy. Prognosis is poor in these patients because the AVM often causes bone destruction and cardiac failure. Genetic mutations in rasa-1 are associated with multiple arteriovenous malformations in capillary malformation-AVM syndrome.16
CUTIS MARMORATA TELANGIECTATIC CONGENITA
Cutis marmorata telangiectatic congenita (CMTC) is a form of vascular malformation comprised of capillaries and veins that presents at birth as a netlike arrangement of nonblanching mottling resembling livedo. Atrophy of associated skin and ulceration can occur within the lesions. Port wine stains (PWSs) in other sites are the most common associated finding (eFig. 364.2 ).